Project Summary/Abstract: Heart failure (HF) patients show multiple neuropsychological and cardiovascular abnormalities which indicate changes in brain function. Brain injury, defined as loss of tissue and changes in tissue properties and function, occurs in areas which regulate mood, memory, blood pressure, heart rate, and breathing. All of these symptoms have been linked to increased morbidity and mortality in HF. However, the processes which elicit this brain injury are uncertain. Sleep-disordered breathing (SDB) characterized by repetitive hypoxia/reperfusion of oxygen and intermittent ischemia is common in HF, and may contribute significantly to brain damage found in the syndrome. However, the relationship between SDB and the extent and location of brain injury in HF patients is not established. We hypothesize that processes accompanying ischemia and hypoxia, and subsequent reperfusion associated with sleep-disordered breathing (SDB) in HF initiate and exacerbate the brain injury. We will 1) demonstrate that the extent of gray matter damage (assessed by structural magnetic resonance imaging, including mean diffusivity and fractional anisotropy) in HF depends on the presence of SDB (assessed via overnight polysomnography); 2) show that nerve fibers (white matter - evaluated via structural MRI and fiber tracking techniques) interconnecting major autonomic control structures are injured in HF patients with SDB; and 3) Determine whether the extent of brain injury (gray matter damage and white matter integrity) relates to aspects of deoxygenation/oxygen reperfusion during SDB, and whether such disordered breathing is more injurious during particular sleep states, or with more-frequent oxygen reperfusion. Using 2-group comparative and correlational designs, 80 subjects (30 HF subjects with SDB, 30 HF subjects without SDB, 20 healthy controls without SDB) will undergo structural MRI and overnight polysomnography studies. Inclusion criteria for all subjects will be age 40 - 65 yrs; HF will be systolic dilated, and LVEF < 0.40. Exclusion criteria for all subjects include claustrophobia, presence of loose metal (for example, pacemakers, braces, implanted hearing aids, or embolic coils). Statistical tests will consist of T-tests and Pearson's correlations with significance set at p < 0.05. The objective is to determine whether SDB is associated with alterations in brain structure in HF, and whether oxygenation/reperfusion processes accompanying apnea could lead to brain injuries in the syndrome. Determining the ongoing detrimental processes which cause brain damage in HF is essential to develop innovative treatments to reduce or prevent brain injury which can exacerbate the autonomic, cognitive, and mood deficits in this high-risk patient population.